Journal of Perinatology (2015) 35, 607–611 © 2015 Nature America, Inc. All rights reserved 0743-8346/15 www.nature.com/jp
ORIGINAL ARTICLE
Definitive peritoneal drainage in the extremely low birth weight infant with spontaneous intestinal perforation: predictors and hospital outcomes BM Jakaitis1 and AM Bhatia1,2 OBJECTIVE: To identify characteristics associated with definitive peritoneal drainage (PD) in the extremely low birth weight infant diagnosed with spontaneous intestinal perforation (SIP). We also sought to determine whether patients requiring a second operation (salvage laparotomy) following PD are at increased risk of adverse hospital outcomes, including increased times to full enteral feedings and decreased 30-day survival. STUDY DESIGN: We performed a retrospective chart review of infants with a birth weight o1000 g who underwent PD for SIP at a single tertiary neonatal unit from 2003 to 2012. Infants with signs of necrotizing enterocolitis on abdominal plain films, including pneumatosis intestinalis, portal venous gas or fixed, dilated small loops of bowel were excluded from the study. Perinatal and perioperative data and short-term neonatal outcomes prior to hospital discharge were collected. Comparison was made between two groups: infants treated with definitive PD vs infants requiring salvage laparotomy. Data were analyzed using independent samples t-test and Cochrane–Mantel–Haenszel. RESULT: Eighty-nine infants who fit all inclusion criteria were identified during the study period. PD was definitive in 67 (75.3%) patients. Patients who had definitive PD vs those who required salvage laparotomy were significantly more likely to present at a later day of life (9.6 ± 5.3 vs 5.6 ± 2.7, P o 0.0001) and to have a lower birth weight (724.6 g ± 132.5 vs 809.2 g ± 143.1, P = 0.02). The administration of indomethacin or ibuprofen prior to the diagnosis of SIP was also associated with definitive PD (74.6% vs 50%, P = 0.03). Comparison of feeding outcomes revealed that the time to achieve full enteral feeds was significantly longer for those who underwent a salvage laparotomy (95.9 ± 30.2 vs 60.4 ± 30.4 days, P o0.005). Short-term survival (430 days) was not significantly different between the two groups. CONCLUSION: PD was definitive therapy for the majority of neonates included in this study who were referred for surgical evaluation of SIP. Our data point to trends in being able to identify infants with SIP who are at risk for salvage laparotomy following PD, and thus, adverse nutritional outcomes. Larger, prospective studies are needed to further evaluate this specific patient population and identify those patients who are likely to succeed with PD following the diagnosis of SIP. Journal of Perinatology (2015) 35, 607–611; doi:10.1038/jp.2015.23; published online 9 April 2015
INTRODUCTION Spontaneous intestinal perforation (SIP) of the newborn occurs primarily in extremely low birth weight infants, or those infants with a birth weight o1000 g, with an incidence of ~ 3% in this specific population.1,2 In addition to feeding difficulties and prolonged hospitalization, infants diagnosed with SIP are at increased risk for long-term neurodevelopmental impairment.1,3,4 The affected patient typically presents early in life with an abrupt onset of abdominal distention and occasionally a bluish discoloration of the abdomen5 prior to or shortly after beginning enteral feeds.6–10 Although it can be difficult to distinguish SIP from necrotizing enterocolitis (NEC) based on clinical presentation, the distinct histopathology11–14 of an isolated or focal perforation makes SIP recognizable as a disease process separate from NEC. Widespread recognition of SIP began in the 1980’s following the advent of indomethacin therapy for patent ductus arteriosus closure,15–18 but the exact etiology remains unknown to date. Well-known risk factors for SIP include extreme prematurity and 1
the concurrent use of steroids and indomethacin in the early postnatal period.2 In 1977, Ein et al.19 reported on the treatment of five patients suffering from intestinal perforation with peritoneal drainage (PD). Of the five patients, three survived and one of the three required a reoperation. Three years later, Janik and Ein presented data showing definitive PD for a number of patients with intestinal perforation, which led them to propose that infants weighing o1000 g who were too unstable for a laparotomy should undergo PD.20 Since that time, PD has become an accepted option for the extremely low birth weight infant suffering from an intestinal perforation felt to be either spontaneous,21,22 or secondary to NEC.23–25 The majority of extremely low birth weight infants at our institution who are suspected to have a diagnosis of SIP at presentation are treated with PD with the hope that it will be a definitive and less invasive therapy. An unknown percentage of these patients eventually fail PD and undergo a salvage laparotomy. Little is known about risk factors associated with PD failure and outcomes following salvage laparotomy in patients
Pediatric Surgery, Emory University School of Medicine, Atlanta, GA, USA and 2Children’s Healthcare of Atlanta, Atlanta, GA, USA. Correspondence: Dr AM Bhatia, Pediatric Surgery, Emory University School of Medicine, 1975 Century Blvd. NE, Suite #6, Atlanta, GA 30345, USA. E-mail: [email protected] Received 7 November 2014; revised 9 February 2015; accepted 11 February 2015; published online 9 April 2015
Peritoneal drainage for intestinal perforation BM Jakaitis and AM Bhatia
608 with SIP. One previous small study (n = 16) showed that extremely low birth weight infants with SIP who failed PD had a significantly higher percentage of bands in the white blood cell count prior to drain placement and more frequently required vasopressor therapy at the time of presentation and during the 48 h following peritoneal drain placement.26 In our retrospective cohort study, we aimed to identify preoperative and perioperative characteristics, which could identify those infants who succeed with PD alone and those who are at risk of PD failure in our patient population. In addition, we compared hospital outcomes between infants with definitive PD and infants requiring salvage laparotomy. METHODS Inclusion criteria After institutional review board approval was obtained (Emory University #IRB00060431), a retrospective cohort study was conducted at Children’s Healthcare of Atlanta at Egleston, a regional tertiary surgical referral center. Neonatal intensive care unit admission records were queried for patients with an admitting diagnosis of intestinal perforation from 2003 to 2012. Neonates with a birth weight of o 1000 g who received a peritoneal drain as initial therapy for SIP were included in the study. Furthermore, patients were only included if their clinical course was consistent with SIP, defined as the sudden onset of abdominal distention with pneumoperitoneum or a gasless abdomen on abdominal plain films and having had little (o30 ml kg − 1 per day) to no enteral feeds started. Radiologic plain films prior to PD were reviewed. Exclusion criteria, based on interpretation by a radiologist, included the presence of pneumatosis intestinalis, portal venous gas or fixed, dilated small loops of bowel.
Data collection Objective data in the maternal, birth and patient history prior to and at the time of admission to our facility was obtained. Operative notes for PD and salvage laparotomy (when applicable) for all patients were reviewed and all findings recorded. Specifically, PD operative notes were evaluated for the type of fluid, if any, obtained when the abdomen was entered. For patients who received a laparotomy, pathology, when available, was reviewed. We also collected postoperative data to evaluate hospital outcomes. Information gathered included days spent on mechanical ventilation and total parental nutrition, time to achieve full enteral feeds (defined as 140 ml kg − 1 per day), hospital length-of-stay and survival to 30 days after PD.
Statistical analysis Preoperative and perioperative characteristics and postoperative data were compared between patients treated with definitive PD and those treated with PD plus salvage laparotomy. PD was considered definitive if the patient was discharged home or died without a laparotomy. Categorical data was evaluated by Cochrane–mantel–Haenszel, whereas independent samples t-test was utilized for numerical or continuous variables. Continuous variables are reported as mean ± s.d. of the mean. In addition to comparing the two groups with all study patients included, similar analysis was carried out after stratification of patients according to birth weight (o750 g and 751 to 999 g). A P-value o 0.05 was considered statistically significant.
Peritoneal drain placement Peritoneal drains were placed by the pediatric surgeon at the bedside in the neonatal intensive care unit. Patients received sedation and analgesia as deemed appropriate by the neonatologist. Small incision(s) were placed in the lower abdominal quadrant(s) and the peritoneal cavity was entered with a hemostat. All fluid and air was evacuated through the incision(s). Either one or two ¼ inch penrose drains were placed and secured.
RESULTS PD failure rates and mortality After review of the medical records, we identified 89 patients diagnosed with SIP who met all inclusion criteria. Of the cohort, 67 Journal of Perinatology (2015), 607 – 611
(75.3%) were treated with definitive PD and 22 (24.7%) required a salvage laparotomy. The 30-day survival rates for the PD and salvage laparotomy groups were 82% and 95%, respectively (P = 0.27) (and Table 4). When patients were stratified according to birth weight (o 750 g and 750 to 999 g) there was no significant difference in mortality between the groups. Six patients (five in PD group and one in salvage laparotomy group) were lost to followup and were not included in the 30-day mortality calculation. These patients were transferred back to their referring facility within 30 days of initial PD, and information about their clinical course following transfer was not available. While we do not know survival data on these patients, it is unlikely that patients in the PD group lost to follow-up did not receive a salvage laparotomy because they would have returned to our facility for the operation. Reasons for death prior to 30 days of life in the PD group included withdrawal of support or redirection of care (n = 7; four for IVH and three for clinical decompensation), respiratory failure (n = 2) and sepsis (n = 1). The one death in the salvage laparotomy group prior to 30 days was secondary to withdrawal of support. Preoperative characteristics Comparison (Table 1) of preoperative data and clinical course prior to PD between the two groups revealed that infants with a younger gestational age and lower birth weight were significantly more likely to have definitive PD following SIP. The relative risk of needing salvage laparotomy for infants with a birth weight of
Table 1.
Comparison of preoperative characteristics
Characteristic
PD
PD + LAP
P-value
n 67 22 Maternal age, years 26.0 ± 5.7 28.9 ± 6.7 0.08 Rupture of membranes 16.4 31.8 0.10 424 h, % Cesarean section, % 56.7 59.1 0.68 Antenatal steroids, % 64.2 77.3 0.34 Twin gestation, % 29.9 36.4 0.68 Male sex, % 56.7 68.2 0.62 Gestational age, weeks 25.1 ± 1.3 25.8 ± 1.2 0.02 Birth weight, grams 724.6 ± 132.5 809.2 ± 143.1 0.02 o750 grams, % 34.8 14.0 0.02 APGAR (1 min) 3.5 ± 2.5 4 ± 2.6 0.46 APGAR (5 min) 6.1 ± 2.2 5.8 ± 2.6 0.62 Enteral/trophic feeds 53.7 45.5 0.48 started, % Received NSAIDS, % 74.6 50 0.03 Received postnatal 23.9 13.6 0.29 steroids, % Day of life at perforation, 9.6 ± 5.3 5.6 ± 2.7 o0.0001 days Day of Life ⩽ 7 days at 38.8 77.3 0.0035 perforation, % Intraventricular hemorrhage 38.8 36.4 0.24 (grade 3 or 4), % 22.3 ± 15 20.2 ± 15.7 0.59 White blood cell count, 1000 μl − 1 Bands, % of WBC count 7.3 ± 8.9 9 ± 8.7 0.48 Mean arterial pressure, 39.2 ± 12.2 44.5 ± 11.8 0.13 mmHg Heart rate, bpm 160.5 ± 20.6 156.1 ± 12.3 0.37 Platelets, 1000 μl − 1 190.8 ± 100 157.9 ± 76.7 0.19 pH 7.26 ± 0.10 7.25 ± 0.15 0.93 Base deficit, meq 5.2 ± 4.0 5.3 ± 5.7 0.96 Positive blood culture, % 28.4 31.8 0.24 Vasopressor requirement, % 55.2 40.9 0.15 Abbreviations: bpm, beats per minute; LAP, laparotomy; PD, peritoneal drainage; NSAIDS, nonsteroidal anti-inflammatory drugs; WBC, white blood cells.
© 2015 Nature America, Inc.
Peritoneal drainage for intestinal perforation BM Jakaitis and AM Bhatia
o750 g was 0.6 (95% confidence interval 0.4 to 0.9). In addition, patients who presented at a later day of life were significantly more likely to succeed with PD alone, and those presenting before or at 7 days of life were more likely (relative risk 2.7, 95% confidence interval 1.2 to 6.1) to go on to need a salvage laparotomy. Whether or not a patient received indomethacin or ibuprofen (prophylaxis and treatment for PDA were combined) prior to presentation also reached statistical significance, with patients who received nonsteroidal anti-inflammatory drugs being more likely to require only PD (P = 0.03). Intraoperative findings There were no significant differences in the intraoperative findings at the time of peritoneal drain placement. The presence of stool upon entering the abdomen did have a large difference in the percentage of patients between the two groups with a higher percentage of patients with stool present going on to need salvage laparotomy (71.4% vs 51.5%) (Table 2). The opposite was true of the finding of serous fluid in the abdomen, with a higher percentage of patients having definitive drainage with PD alone if they had serous fluid. However, these percentages were not statistically different. Reasons for PD failure and drain complications We found four main reasons for failure after PD (Table 3). The majority of patients who failed PD (19 of 22) fit well into two broad categories based on how long they waited for a salvage laparotomy. Early failure occurred in the first 10 days (mean = 5.8 days) after PD secondary to sepsis or persistent pneumoperitoneum. Late failure ensued at an average of 13.1 days after PD. These late failures were due to recurrent pneumoperitoneum or enterocutaneous fistula. Pathology was available for 14 of the 22 patients who failed PD and required salvage laparotomy. Four patients were found to have pathology consistent with NEC and four patients had inspissated meconium in the lumen of the small intestine (Table 3). There were 13 drain complications in 12 patients, with 5 of the patients being in the salvage laparotomy group. These complications included hernia (5), evisceration (6), retained foreign body (1) and abscess (1).
Table 2.
Intraoperative findings with peritoneal drainage
Stool, % Black or dark fluid, % Bloody output, % Serous output, % Positive peritoneal culture, %
PD
PD + LAP
P-value
51.5 6.0 6.1 36.4 40.9
71.4 14.2 4.8 19.0 33.3
0.10 0.17 0.91 0.10 0.71
Abbreviation: LAP, laparotomy.
Table 3.
609 Hospital outcomes Patients (Table 4) who underwent a salvage laparotomy had significantly longer times (measured from the date of PD) to beginning enteral feeds and also took significantly more days to achieve full enteral feeds (defined as 140 ml kg − 1 per day). Infants who succeeded with PD alone spent a significantly less amount of time on total parental nutrition than those who required salvage laparotomy. Total days spent on mechanical ventilation and lengths of hospital stay were not significantly different between the two groups. DISCUSSION Without clear evidence to guide therapy toward PD or laparotomy as a superior surgical option for premature infants with intestinal perforation, the debate persists over which intervention should be used initially for our fragile patients. Two randomized, controlled trials comparing PD and laparotomy as initial therapy for intestinal perforation in very low birth weight infants failed to show a difference in both mortality and dependence on total parenteral nutrition.27–29 However, neither study made a clear distinction between or analyzed separately patients who presented with a clinical course consistent with SIP as opposed to NEC. The histopathology of these two disease processes makes it clear that they are dissimilar, with SIP lacking the inflammation and ischemia that is a hallmark of NEC.11 Furthermore, SIP patients tend to present earlier in life (average of 7 days) and do not develop pneumatosis intestinalis or necrosis of their intestines. Despite their differences, the difficulty in correctly identifying one disease state over the other at the time of presentation does need to be acknowledged. It has previously been shown that the predictive value of radiologic findings is low, as the sensitivity of the presence of pneumatosis intestinalis on plain films for NEC is only 44%.30 For this reason, we combined the clinical course prior to presentation with radiologic findings to make up our cohort. Even with this effort, we discovered pathology consistent with NEC in 4 out of 22 patients in the salvage laparotomy group. We do not believe that this difficulty should deter studies from attempting to separate these two groups of patients. By conducting studies designed specifically for infants with SIP we may be able to optimize our surgical and therapeutic approach to this group of patients. Within our specified group of neonates with an initial diagnosis of SIP, we have shown a relatively high rate of definitive PD (75.3%). This percentage is higher than the studies by Moss et al.27 and Rees et al.,28 who showed definitive PD rates of 62 and 26%, respectively. When comparing our study to a recent and similar (although smaller sample size) study looking at SIP patients treated with PD by Emil et al.,26 the difference is striking. Their rate of definitive PD was only 31% (5/16). Among other studies looking at SIP patients alone, the rate of definitive PD ranges from 55 to 80%.21,25,31,32 Interpretation of this specific outcome is challenging with many studies performed at multiple centers. Numerous
Patterns of peritoneal drainage failure
Reason for failure
n
Days after PDa
Pathology with NECb
Pathology with meconiumb
Persistent pneumoperitoneum Sepsis Recurrent pneumoperitoneum Enterocutaneous fistula Otherc Total or average
2 5 7 5 3 22
4 6.6 13.8 12.3 32 (1–89) 13.3
0 2 0 2 0 4
1 0 2 1 0 4
Abbreviation: NEC, necrotizing enterocolitis. amean. bPathology available for 14 of 22 patients. cHemorrhage, evisceration with visible hole, small bowel obstruction.
© 2015 Nature America, Inc.
Journal of Perinatology (2015), 607 – 611
Peritoneal drainage for intestinal perforation BM Jakaitis and AM Bhatia
610 Table 4.
Comparison of short-term outcomes PD
PD + LAP
P-value
Time to initiate enteral feeds, 20.1 ± 10.2 26.1 ± 9.0 o 0.05 days 60.4 ± 30.4 95.9 ± 30.2 o 0.005 Time to achieve full enteral feeds,a days Total time spent on TPN, days 62.7 ± 32.9 94.3 ± 28.7 0.015 Total time spent on CMV or 27.4 ± 20.2 31.9 ± 18.2 0.49 HFOV Time to discharge, days 120.3 ± 33.9 144.5 ± 38.5 0.08 Survival ⩾ 30 days, % 82 95 0.27 Abbreviations: CMV, conventional mechanical ventilation; HFOV, high frequency oscillatory ventilation; LAP, laparotomy; PD, peritoneal drainage; TPN, total parenteral nutrition. aDefined as 130 ml kg − 1 day of enteral feeds
variables can and will influence the success rate of PD, including the preferences and biases of attending pediatric surgeons and neonatologists. Some groups or practices will have a low threshold for reoperation as in the studies by Rees et al.28 and Emil et al.,26 whereas others will wait longer to intervene. At our institution, when a peritoneal drain is placed in an infant suspected to have SIP, it is done with the hope that it will be a definitive therapy. In the literature, the ideal use of PD for perforation continues to be debated. There are advocates for the use of PD as a bridge therapy to laparotomy for those infants who are felt to be too sick for an initial laparotomy,8,28,32–37 whereas others have advanced the idea of PD as definitive therapy.21,22,25,31,38 In addition to the demonstration of a large proportion of our patients doing well with PD alone, we uncovered characteristics that may be used to identify who these patients are. The categories of birth weight o 750 g and presentation after 7 days of life both had significantly higher rates of definitive PD. Also, those who had received any form of nonsteroidal antiinflammatory drug therapy prior to diagnosis were more likely to avoid a laparotomy. Although the presence of stool or meconium at the time of drain placement was not statistically significant, a large percentage of patients in the salvage laparotomy group had this finding (P = 0.1). Furthermore, four patients in the salvage laparotomy group had meconium plugging on pathology report. This may be of importance because it seems unlikely that PD alone would be sufficient to treat a patient with this specific finding on pathology. Surprisingly, we did not find any significant differences in the laboratory values between the two groups at the time of presentation. This is in contrast to previous studies and what we expected to find. Tepas et al.39 found that the presence of ‘metabolic derangement’ was associated with better outcomes following laparotomy rather than PD. Emil et al.26 revealed that infants requiring a laparotomy in addition to PD more often needed vasopressor support at presentation and in the 48 h following PD and had a higher percentage of bands in the white blood cell count. Owing to the retrospective nature of our study, precise review of postoperative vital signs was limited. The ability to predict a patient’s response to PD based on vital signs and laboratory values consistent with metabolic instability is an important question and deserves to be studied further. We believe that uncovering patient attributes that can be associated with definitive PD is worth investigating. The intervention of PD, which avoids the complications of laparotomy, will most likely continue to be used for infants o 1000 g. Identification of certain patients who may not do well with PD will give the surgeon more objective information and may lead to a lower threshold to perform a primary laparotomy. Our data indicate that Journal of Perinatology (2015), 607 – 611
those patients who undergo a second operation are at risk for adverse hospital outcomes, specifically regarding nutritional parameters, which included longer times spent on total parenteral nutrition and longer times to achieve full enteral feeds. Although not proven, others have speculated that prolonged management with a peritoneal drain may lead to an increased cytokine response and, subsequently, adverse neurodevelopmental outcomes.2 Weaknesses of our study include the retrospective nature in which we collected the data. We had many patients who were transferred back to their referral facility prior to discharge and, therefore, we were unable to assess some of their hospital outcomes. We did have an excess, although not significant, of mortality in the definitive PD group. This was in part attributed to the withdrawal of support in a number of patients, making it difficult to interpret the survival data. With a long study period of 10 years, there have likely been many practice changes within both the surgery and the neonatology divisions, leading to different care practices between study patients. Nevertheless, we do feel that our study contributes toward indentifying an ideal subgroup of patients in which to utilize PD. Our data indicate that there may be a subset of patients among those diagnosed with SIP who have a specific type of perforation amenable to PD. Larger, prospective trials would be needed to confirm our findings. Further understanding about how to differentiate between SIP and NEC will also aid in this endeavor. For example, studies such as Chan et al.40 and Bhatia et al.,41 which show a difference in cytokine profiles between the two diseases, may prove to be very helpful in future diagnosis. Optimal care of premature infants with acquired neonatal intestinal disease relies on quality investigation into how to best utilize the limited therapies we have available.42,43 CONFLICT OF INTEREST The authors declare no conflict of interest.
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Journal of Perinatology (2015), 607 – 611
ORIGINAL ARTICLE
Definitive peritoneal drainage in the extremely low birth weight infant with spontaneous intestinal perforation: predictors and hospital outcomes BM Jakaitis1 and AM Bhatia1,2 OBJECTIVE: To identify characteristics associated with definitive peritoneal drainage (PD) in the extremely low birth weight infant diagnosed with spontaneous intestinal perforation (SIP). We also sought to determine whether patients requiring a second operation (salvage laparotomy) following PD are at increased risk of adverse hospital outcomes, including increased times to full enteral feedings and decreased 30-day survival. STUDY DESIGN: We performed a retrospective chart review of infants with a birth weight o1000 g who underwent PD for SIP at a single tertiary neonatal unit from 2003 to 2012. Infants with signs of necrotizing enterocolitis on abdominal plain films, including pneumatosis intestinalis, portal venous gas or fixed, dilated small loops of bowel were excluded from the study. Perinatal and perioperative data and short-term neonatal outcomes prior to hospital discharge were collected. Comparison was made between two groups: infants treated with definitive PD vs infants requiring salvage laparotomy. Data were analyzed using independent samples t-test and Cochrane–Mantel–Haenszel. RESULT: Eighty-nine infants who fit all inclusion criteria were identified during the study period. PD was definitive in 67 (75.3%) patients. Patients who had definitive PD vs those who required salvage laparotomy were significantly more likely to present at a later day of life (9.6 ± 5.3 vs 5.6 ± 2.7, P o 0.0001) and to have a lower birth weight (724.6 g ± 132.5 vs 809.2 g ± 143.1, P = 0.02). The administration of indomethacin or ibuprofen prior to the diagnosis of SIP was also associated with definitive PD (74.6% vs 50%, P = 0.03). Comparison of feeding outcomes revealed that the time to achieve full enteral feeds was significantly longer for those who underwent a salvage laparotomy (95.9 ± 30.2 vs 60.4 ± 30.4 days, P o0.005). Short-term survival (430 days) was not significantly different between the two groups. CONCLUSION: PD was definitive therapy for the majority of neonates included in this study who were referred for surgical evaluation of SIP. Our data point to trends in being able to identify infants with SIP who are at risk for salvage laparotomy following PD, and thus, adverse nutritional outcomes. Larger, prospective studies are needed to further evaluate this specific patient population and identify those patients who are likely to succeed with PD following the diagnosis of SIP. Journal of Perinatology (2015) 35, 607–611; doi:10.1038/jp.2015.23; published online 9 April 2015
INTRODUCTION Spontaneous intestinal perforation (SIP) of the newborn occurs primarily in extremely low birth weight infants, or those infants with a birth weight o1000 g, with an incidence of ~ 3% in this specific population.1,2 In addition to feeding difficulties and prolonged hospitalization, infants diagnosed with SIP are at increased risk for long-term neurodevelopmental impairment.1,3,4 The affected patient typically presents early in life with an abrupt onset of abdominal distention and occasionally a bluish discoloration of the abdomen5 prior to or shortly after beginning enteral feeds.6–10 Although it can be difficult to distinguish SIP from necrotizing enterocolitis (NEC) based on clinical presentation, the distinct histopathology11–14 of an isolated or focal perforation makes SIP recognizable as a disease process separate from NEC. Widespread recognition of SIP began in the 1980’s following the advent of indomethacin therapy for patent ductus arteriosus closure,15–18 but the exact etiology remains unknown to date. Well-known risk factors for SIP include extreme prematurity and 1
the concurrent use of steroids and indomethacin in the early postnatal period.2 In 1977, Ein et al.19 reported on the treatment of five patients suffering from intestinal perforation with peritoneal drainage (PD). Of the five patients, three survived and one of the three required a reoperation. Three years later, Janik and Ein presented data showing definitive PD for a number of patients with intestinal perforation, which led them to propose that infants weighing o1000 g who were too unstable for a laparotomy should undergo PD.20 Since that time, PD has become an accepted option for the extremely low birth weight infant suffering from an intestinal perforation felt to be either spontaneous,21,22 or secondary to NEC.23–25 The majority of extremely low birth weight infants at our institution who are suspected to have a diagnosis of SIP at presentation are treated with PD with the hope that it will be a definitive and less invasive therapy. An unknown percentage of these patients eventually fail PD and undergo a salvage laparotomy. Little is known about risk factors associated with PD failure and outcomes following salvage laparotomy in patients
Pediatric Surgery, Emory University School of Medicine, Atlanta, GA, USA and 2Children’s Healthcare of Atlanta, Atlanta, GA, USA. Correspondence: Dr AM Bhatia, Pediatric Surgery, Emory University School of Medicine, 1975 Century Blvd. NE, Suite #6, Atlanta, GA 30345, USA. E-mail: [email protected] Received 7 November 2014; revised 9 February 2015; accepted 11 February 2015; published online 9 April 2015
Peritoneal drainage for intestinal perforation BM Jakaitis and AM Bhatia
608 with SIP. One previous small study (n = 16) showed that extremely low birth weight infants with SIP who failed PD had a significantly higher percentage of bands in the white blood cell count prior to drain placement and more frequently required vasopressor therapy at the time of presentation and during the 48 h following peritoneal drain placement.26 In our retrospective cohort study, we aimed to identify preoperative and perioperative characteristics, which could identify those infants who succeed with PD alone and those who are at risk of PD failure in our patient population. In addition, we compared hospital outcomes between infants with definitive PD and infants requiring salvage laparotomy. METHODS Inclusion criteria After institutional review board approval was obtained (Emory University #IRB00060431), a retrospective cohort study was conducted at Children’s Healthcare of Atlanta at Egleston, a regional tertiary surgical referral center. Neonatal intensive care unit admission records were queried for patients with an admitting diagnosis of intestinal perforation from 2003 to 2012. Neonates with a birth weight of o 1000 g who received a peritoneal drain as initial therapy for SIP were included in the study. Furthermore, patients were only included if their clinical course was consistent with SIP, defined as the sudden onset of abdominal distention with pneumoperitoneum or a gasless abdomen on abdominal plain films and having had little (o30 ml kg − 1 per day) to no enteral feeds started. Radiologic plain films prior to PD were reviewed. Exclusion criteria, based on interpretation by a radiologist, included the presence of pneumatosis intestinalis, portal venous gas or fixed, dilated small loops of bowel.
Data collection Objective data in the maternal, birth and patient history prior to and at the time of admission to our facility was obtained. Operative notes for PD and salvage laparotomy (when applicable) for all patients were reviewed and all findings recorded. Specifically, PD operative notes were evaluated for the type of fluid, if any, obtained when the abdomen was entered. For patients who received a laparotomy, pathology, when available, was reviewed. We also collected postoperative data to evaluate hospital outcomes. Information gathered included days spent on mechanical ventilation and total parental nutrition, time to achieve full enteral feeds (defined as 140 ml kg − 1 per day), hospital length-of-stay and survival to 30 days after PD.
Statistical analysis Preoperative and perioperative characteristics and postoperative data were compared between patients treated with definitive PD and those treated with PD plus salvage laparotomy. PD was considered definitive if the patient was discharged home or died without a laparotomy. Categorical data was evaluated by Cochrane–mantel–Haenszel, whereas independent samples t-test was utilized for numerical or continuous variables. Continuous variables are reported as mean ± s.d. of the mean. In addition to comparing the two groups with all study patients included, similar analysis was carried out after stratification of patients according to birth weight (o750 g and 751 to 999 g). A P-value o 0.05 was considered statistically significant.
Peritoneal drain placement Peritoneal drains were placed by the pediatric surgeon at the bedside in the neonatal intensive care unit. Patients received sedation and analgesia as deemed appropriate by the neonatologist. Small incision(s) were placed in the lower abdominal quadrant(s) and the peritoneal cavity was entered with a hemostat. All fluid and air was evacuated through the incision(s). Either one or two ¼ inch penrose drains were placed and secured.
RESULTS PD failure rates and mortality After review of the medical records, we identified 89 patients diagnosed with SIP who met all inclusion criteria. Of the cohort, 67 Journal of Perinatology (2015), 607 – 611
(75.3%) were treated with definitive PD and 22 (24.7%) required a salvage laparotomy. The 30-day survival rates for the PD and salvage laparotomy groups were 82% and 95%, respectively (P = 0.27) (and Table 4). When patients were stratified according to birth weight (o 750 g and 750 to 999 g) there was no significant difference in mortality between the groups. Six patients (five in PD group and one in salvage laparotomy group) were lost to followup and were not included in the 30-day mortality calculation. These patients were transferred back to their referring facility within 30 days of initial PD, and information about their clinical course following transfer was not available. While we do not know survival data on these patients, it is unlikely that patients in the PD group lost to follow-up did not receive a salvage laparotomy because they would have returned to our facility for the operation. Reasons for death prior to 30 days of life in the PD group included withdrawal of support or redirection of care (n = 7; four for IVH and three for clinical decompensation), respiratory failure (n = 2) and sepsis (n = 1). The one death in the salvage laparotomy group prior to 30 days was secondary to withdrawal of support. Preoperative characteristics Comparison (Table 1) of preoperative data and clinical course prior to PD between the two groups revealed that infants with a younger gestational age and lower birth weight were significantly more likely to have definitive PD following SIP. The relative risk of needing salvage laparotomy for infants with a birth weight of
Table 1.
Comparison of preoperative characteristics
Characteristic
PD
PD + LAP
P-value
n 67 22 Maternal age, years 26.0 ± 5.7 28.9 ± 6.7 0.08 Rupture of membranes 16.4 31.8 0.10 424 h, % Cesarean section, % 56.7 59.1 0.68 Antenatal steroids, % 64.2 77.3 0.34 Twin gestation, % 29.9 36.4 0.68 Male sex, % 56.7 68.2 0.62 Gestational age, weeks 25.1 ± 1.3 25.8 ± 1.2 0.02 Birth weight, grams 724.6 ± 132.5 809.2 ± 143.1 0.02 o750 grams, % 34.8 14.0 0.02 APGAR (1 min) 3.5 ± 2.5 4 ± 2.6 0.46 APGAR (5 min) 6.1 ± 2.2 5.8 ± 2.6 0.62 Enteral/trophic feeds 53.7 45.5 0.48 started, % Received NSAIDS, % 74.6 50 0.03 Received postnatal 23.9 13.6 0.29 steroids, % Day of life at perforation, 9.6 ± 5.3 5.6 ± 2.7 o0.0001 days Day of Life ⩽ 7 days at 38.8 77.3 0.0035 perforation, % Intraventricular hemorrhage 38.8 36.4 0.24 (grade 3 or 4), % 22.3 ± 15 20.2 ± 15.7 0.59 White blood cell count, 1000 μl − 1 Bands, % of WBC count 7.3 ± 8.9 9 ± 8.7 0.48 Mean arterial pressure, 39.2 ± 12.2 44.5 ± 11.8 0.13 mmHg Heart rate, bpm 160.5 ± 20.6 156.1 ± 12.3 0.37 Platelets, 1000 μl − 1 190.8 ± 100 157.9 ± 76.7 0.19 pH 7.26 ± 0.10 7.25 ± 0.15 0.93 Base deficit, meq 5.2 ± 4.0 5.3 ± 5.7 0.96 Positive blood culture, % 28.4 31.8 0.24 Vasopressor requirement, % 55.2 40.9 0.15 Abbreviations: bpm, beats per minute; LAP, laparotomy; PD, peritoneal drainage; NSAIDS, nonsteroidal anti-inflammatory drugs; WBC, white blood cells.
© 2015 Nature America, Inc.
Peritoneal drainage for intestinal perforation BM Jakaitis and AM Bhatia
o750 g was 0.6 (95% confidence interval 0.4 to 0.9). In addition, patients who presented at a later day of life were significantly more likely to succeed with PD alone, and those presenting before or at 7 days of life were more likely (relative risk 2.7, 95% confidence interval 1.2 to 6.1) to go on to need a salvage laparotomy. Whether or not a patient received indomethacin or ibuprofen (prophylaxis and treatment for PDA were combined) prior to presentation also reached statistical significance, with patients who received nonsteroidal anti-inflammatory drugs being more likely to require only PD (P = 0.03). Intraoperative findings There were no significant differences in the intraoperative findings at the time of peritoneal drain placement. The presence of stool upon entering the abdomen did have a large difference in the percentage of patients between the two groups with a higher percentage of patients with stool present going on to need salvage laparotomy (71.4% vs 51.5%) (Table 2). The opposite was true of the finding of serous fluid in the abdomen, with a higher percentage of patients having definitive drainage with PD alone if they had serous fluid. However, these percentages were not statistically different. Reasons for PD failure and drain complications We found four main reasons for failure after PD (Table 3). The majority of patients who failed PD (19 of 22) fit well into two broad categories based on how long they waited for a salvage laparotomy. Early failure occurred in the first 10 days (mean = 5.8 days) after PD secondary to sepsis or persistent pneumoperitoneum. Late failure ensued at an average of 13.1 days after PD. These late failures were due to recurrent pneumoperitoneum or enterocutaneous fistula. Pathology was available for 14 of the 22 patients who failed PD and required salvage laparotomy. Four patients were found to have pathology consistent with NEC and four patients had inspissated meconium in the lumen of the small intestine (Table 3). There were 13 drain complications in 12 patients, with 5 of the patients being in the salvage laparotomy group. These complications included hernia (5), evisceration (6), retained foreign body (1) and abscess (1).
Table 2.
Intraoperative findings with peritoneal drainage
Stool, % Black or dark fluid, % Bloody output, % Serous output, % Positive peritoneal culture, %
PD
PD + LAP
P-value
51.5 6.0 6.1 36.4 40.9
71.4 14.2 4.8 19.0 33.3
0.10 0.17 0.91 0.10 0.71
Abbreviation: LAP, laparotomy.
Table 3.
609 Hospital outcomes Patients (Table 4) who underwent a salvage laparotomy had significantly longer times (measured from the date of PD) to beginning enteral feeds and also took significantly more days to achieve full enteral feeds (defined as 140 ml kg − 1 per day). Infants who succeeded with PD alone spent a significantly less amount of time on total parental nutrition than those who required salvage laparotomy. Total days spent on mechanical ventilation and lengths of hospital stay were not significantly different between the two groups. DISCUSSION Without clear evidence to guide therapy toward PD or laparotomy as a superior surgical option for premature infants with intestinal perforation, the debate persists over which intervention should be used initially for our fragile patients. Two randomized, controlled trials comparing PD and laparotomy as initial therapy for intestinal perforation in very low birth weight infants failed to show a difference in both mortality and dependence on total parenteral nutrition.27–29 However, neither study made a clear distinction between or analyzed separately patients who presented with a clinical course consistent with SIP as opposed to NEC. The histopathology of these two disease processes makes it clear that they are dissimilar, with SIP lacking the inflammation and ischemia that is a hallmark of NEC.11 Furthermore, SIP patients tend to present earlier in life (average of 7 days) and do not develop pneumatosis intestinalis or necrosis of their intestines. Despite their differences, the difficulty in correctly identifying one disease state over the other at the time of presentation does need to be acknowledged. It has previously been shown that the predictive value of radiologic findings is low, as the sensitivity of the presence of pneumatosis intestinalis on plain films for NEC is only 44%.30 For this reason, we combined the clinical course prior to presentation with radiologic findings to make up our cohort. Even with this effort, we discovered pathology consistent with NEC in 4 out of 22 patients in the salvage laparotomy group. We do not believe that this difficulty should deter studies from attempting to separate these two groups of patients. By conducting studies designed specifically for infants with SIP we may be able to optimize our surgical and therapeutic approach to this group of patients. Within our specified group of neonates with an initial diagnosis of SIP, we have shown a relatively high rate of definitive PD (75.3%). This percentage is higher than the studies by Moss et al.27 and Rees et al.,28 who showed definitive PD rates of 62 and 26%, respectively. When comparing our study to a recent and similar (although smaller sample size) study looking at SIP patients treated with PD by Emil et al.,26 the difference is striking. Their rate of definitive PD was only 31% (5/16). Among other studies looking at SIP patients alone, the rate of definitive PD ranges from 55 to 80%.21,25,31,32 Interpretation of this specific outcome is challenging with many studies performed at multiple centers. Numerous
Patterns of peritoneal drainage failure
Reason for failure
n
Days after PDa
Pathology with NECb
Pathology with meconiumb
Persistent pneumoperitoneum Sepsis Recurrent pneumoperitoneum Enterocutaneous fistula Otherc Total or average
2 5 7 5 3 22
4 6.6 13.8 12.3 32 (1–89) 13.3
0 2 0 2 0 4
1 0 2 1 0 4
Abbreviation: NEC, necrotizing enterocolitis. amean. bPathology available for 14 of 22 patients. cHemorrhage, evisceration with visible hole, small bowel obstruction.
© 2015 Nature America, Inc.
Journal of Perinatology (2015), 607 – 611
Peritoneal drainage for intestinal perforation BM Jakaitis and AM Bhatia
610 Table 4.
Comparison of short-term outcomes PD
PD + LAP
P-value
Time to initiate enteral feeds, 20.1 ± 10.2 26.1 ± 9.0 o 0.05 days 60.4 ± 30.4 95.9 ± 30.2 o 0.005 Time to achieve full enteral feeds,a days Total time spent on TPN, days 62.7 ± 32.9 94.3 ± 28.7 0.015 Total time spent on CMV or 27.4 ± 20.2 31.9 ± 18.2 0.49 HFOV Time to discharge, days 120.3 ± 33.9 144.5 ± 38.5 0.08 Survival ⩾ 30 days, % 82 95 0.27 Abbreviations: CMV, conventional mechanical ventilation; HFOV, high frequency oscillatory ventilation; LAP, laparotomy; PD, peritoneal drainage; TPN, total parenteral nutrition. aDefined as 130 ml kg − 1 day of enteral feeds
variables can and will influence the success rate of PD, including the preferences and biases of attending pediatric surgeons and neonatologists. Some groups or practices will have a low threshold for reoperation as in the studies by Rees et al.28 and Emil et al.,26 whereas others will wait longer to intervene. At our institution, when a peritoneal drain is placed in an infant suspected to have SIP, it is done with the hope that it will be a definitive therapy. In the literature, the ideal use of PD for perforation continues to be debated. There are advocates for the use of PD as a bridge therapy to laparotomy for those infants who are felt to be too sick for an initial laparotomy,8,28,32–37 whereas others have advanced the idea of PD as definitive therapy.21,22,25,31,38 In addition to the demonstration of a large proportion of our patients doing well with PD alone, we uncovered characteristics that may be used to identify who these patients are. The categories of birth weight o 750 g and presentation after 7 days of life both had significantly higher rates of definitive PD. Also, those who had received any form of nonsteroidal antiinflammatory drug therapy prior to diagnosis were more likely to avoid a laparotomy. Although the presence of stool or meconium at the time of drain placement was not statistically significant, a large percentage of patients in the salvage laparotomy group had this finding (P = 0.1). Furthermore, four patients in the salvage laparotomy group had meconium plugging on pathology report. This may be of importance because it seems unlikely that PD alone would be sufficient to treat a patient with this specific finding on pathology. Surprisingly, we did not find any significant differences in the laboratory values between the two groups at the time of presentation. This is in contrast to previous studies and what we expected to find. Tepas et al.39 found that the presence of ‘metabolic derangement’ was associated with better outcomes following laparotomy rather than PD. Emil et al.26 revealed that infants requiring a laparotomy in addition to PD more often needed vasopressor support at presentation and in the 48 h following PD and had a higher percentage of bands in the white blood cell count. Owing to the retrospective nature of our study, precise review of postoperative vital signs was limited. The ability to predict a patient’s response to PD based on vital signs and laboratory values consistent with metabolic instability is an important question and deserves to be studied further. We believe that uncovering patient attributes that can be associated with definitive PD is worth investigating. The intervention of PD, which avoids the complications of laparotomy, will most likely continue to be used for infants o 1000 g. Identification of certain patients who may not do well with PD will give the surgeon more objective information and may lead to a lower threshold to perform a primary laparotomy. Our data indicate that Journal of Perinatology (2015), 607 – 611
those patients who undergo a second operation are at risk for adverse hospital outcomes, specifically regarding nutritional parameters, which included longer times spent on total parenteral nutrition and longer times to achieve full enteral feeds. Although not proven, others have speculated that prolonged management with a peritoneal drain may lead to an increased cytokine response and, subsequently, adverse neurodevelopmental outcomes.2 Weaknesses of our study include the retrospective nature in which we collected the data. We had many patients who were transferred back to their referral facility prior to discharge and, therefore, we were unable to assess some of their hospital outcomes. We did have an excess, although not significant, of mortality in the definitive PD group. This was in part attributed to the withdrawal of support in a number of patients, making it difficult to interpret the survival data. With a long study period of 10 years, there have likely been many practice changes within both the surgery and the neonatology divisions, leading to different care practices between study patients. Nevertheless, we do feel that our study contributes toward indentifying an ideal subgroup of patients in which to utilize PD. Our data indicate that there may be a subset of patients among those diagnosed with SIP who have a specific type of perforation amenable to PD. Larger, prospective trials would be needed to confirm our findings. Further understanding about how to differentiate between SIP and NEC will also aid in this endeavor. For example, studies such as Chan et al.40 and Bhatia et al.,41 which show a difference in cytokine profiles between the two diseases, may prove to be very helpful in future diagnosis. Optimal care of premature infants with acquired neonatal intestinal disease relies on quality investigation into how to best utilize the limited therapies we have available.42,43 CONFLICT OF INTEREST The authors declare no conflict of interest.
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